BIOCHEMICAL PHARMACOLOGY
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2026
·
IF 6.5
Cheng Cao,Mubin Sun,Jiabao Li,Zhenyu Yuan,Yuwei Gu,Yufan Shao,Lisheng Wang,Xiaohua Jin,Yijie Cheng,Bo Fan
Urate transporter 1 (URAT1, encoded by SLC22A12 ) is a key mediator of renal urate reabsorption and an important pharmacological target for urate-related disorders. Sodium butyrate (BuNa), a gut microbiota derived short-chain fatty acid, has been implicated in host metabolic regulation, but its role in renal urate transport remains unclear. Here, using molecular docking, cellular thermal shift assays, immunoprecipitation-mass spectrometry and multi-omics analyses, we identified free fatty acid receptor 2 (FFAR2) as a direct target of BuNa in renal proximal tubular HK2 cells . BuNa binding upregulated FFAR2 and promoted URAT1 expression and urate uptake via an FFAR2-dependent pathway. Mechanistically, BuNa/FFAR2 signaling acts via GNAQ to activate PLCβ, generating diacylglycerol and engaging a PKC-dependent p38 MAPK/ELK1 cascade that upregulates arrestin beta 2 (ARRB2). ARRB2 directly binds to IκB, preventing its phosphorylation-dependent degradation, thereby stabilizing IκB and inhibiting NF-κB nuclear translocation. Within the SLC22A12 promoter, NF-κB (RELA/p50) and hepatocyte nuclear factor 1 beta (HNF1β) compete for overlapping binding sites. By blocking NF-κB nuclear entry, BuNa relieves this competition, permitting HNF1β-driven SLC22A12 transcription. Thus, BuNa enhances URAT1-mediated urate reabsorption in HK2 cells via an FFAR2/GNAQ/p38 MAPK/ELK1/ARRB2 axis that stabilizes IκB, suppresses NF-κB, and relieves the competitive binding between NF-κB and HNF1β on the SLC22A12 promoter. These findings establish a previously unrecognized gut microbiota–kidney axis linking microbial BuNa to renal urate homeostasis through a novel transcriptional regulatory circuit.
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NEUROTOXICOLOGY
·
2026
·
IF 3.8
Xuening Li,Linglong Meng,Qiang Niu,Runjiang Ma,Yuhan Li,Hailing Zhou,Xiaoya Fu,Wenjie Chen,Juan Tang,Shangzhi Xu
This study investigated the mechanisms by which a region-specific simulated PM 2.5 from Shihezi, China, exacerbates Alzheimer’s disease (AD) pathology, focusing on the protein kinase B (AKT)/mitogen-activated protein kinase (MAPK) signaling axis. APP/PS1 and wild-type mice were exposed to a simulated Shihezi PM 2.5 suspension. Cognitive function, neuroinflammation, oxidative stress, signaling activity, apoptosis, and amyloid-β (Aβ)/Tau pathology were assessed. Simulated PM 2.5 exposure aggravated cognitive deficits, induced neuroinflammation and oxidative stress, and triggered a significant AKT/MAPK imbalance characterized by MAPK hyperactivation and AKT suppression. This imbalance promoted neuronal apoptosis and exacerbated both Aβ deposition and Tau hyperphosphorylation. Our findings reveal that simulant PM 2.5 -induced neuroinflammation and oxidative stress dysregulate the AKT/MAPK axis, driving neuronal loss and AD progression, and suggest a molecular mechanism by which environmental PM 2.5 exposure may contribute to accelerated neurodegeneration.
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高影响因子
NEUROCHEMICAL RESEARCH
·
2026
·Vol. 51
·期 2
·80
·
IF 4.5
Lu Xuefei,Xu Kai,Zhou Zhenyu,Ding Gaonan,Zhang Yuan,Liang Yongwen,Zhou Jiahui,Jia Minglu,Zhang Yitang,Shen Li,Li Hualing
Alzheimer’s disease (AD) is a progressive neurodegenerative disease for which no effective clinical therapies currently exist. The neuroprotective potential of Chaetoglobosin F (CF), a fungal secondary metabolite, was investigated in this study using a Caenorhabditis elegans ( C. elegans ) model of AD that are transgenic nematodes expressing amyloid-beta (Aβ). Key parameters evaluated included paralysis rate, lifespan, motor and cognitive functions, Aβ plaque aggregation, intracellular reactive oxygen species (ROS), and autophagosome formation. The transcriptional levels of genes were examined by real time PCR. Results showed that treatment with CF significantly delayed paralysis, extended lifespan, and ameliorated Aβ-induced deficits in locomotion and chemotaxis. CF markedly reduced Aβ plaque accumulation, suppressed intracellular ROS levels, and promoted autophagosome formation. Furthermore, CF had potent inhibitory effects on acetylcholinesterase (AChE) activity. These beneficial effects were correlated with the upregulation of crucial genes, including daf-16 , skn-1 , pmk-1 , mtl-1 , unc-51 , bec-1 , lgg-1 , sod-1 and sod-3 , which confirmed the improving antioxidant defenses and autophagy. Our findings demonstrate that CF confers strong neuroprotection against Aβ-induced toxicity in C. elegans by co-regulating oxidative stress and autophagy through the Insulin/IGF-1 (IIS) and p38 MAPK signaling pathways. These results suggest that CF is a promising natural compound for further investigation as a potential therapeutic agent for AD. Graphical
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ACTA PHARMACOLOGICA SINICA
·
2022
·Vol. 43
·期 9
·2289-2301
·
IF 7.169
Su Xue-ling,Wang Shu-hui,Komal Sumra,Cui Liu-gen,Ni Rui-cong,Zhang Li-rong,Han Sheng-na
Connexin 43 (Cx43) is the most important protein in the gap junction channel between cardiomyocytes. Abnormalities of Cx43 change the conduction velocity and direction of cardiomyocytes, leading to reentry and conduction block of the myocardium, thereby causing arrhythmia. It has been shown that IL-1β reduces the expression of Cx43 in astrocytes and cardiomyocytes in vitro. However, whether caspase-1 and IL-1β affect connexin 43 after myocardial infarction (MI) is uncertain. In this study we investigated the effects of VX765, a caspase-1 inhibitor, on the expression of Cx43 and cell-to-cell communication after MI. Rats were treated with VX765 (16 mg/kg, i.v.) 1 h before the left anterior descending artery (LAD) ligation, and then once daily for 7 days. The ischemic heart was collected for histochemical analysis and Western blot analysis. We showed that VX765 treatment significantly decreased the infarct area, and alleviated cardiac dysfunction and remodeling by suppressing the NLRP3 inflammasome/caspase-1/IL-1β expression in the heart after MI. In addition, VX765 treatment markedly raised Cx43 levels in the heart after MI. In vitro experiments were conducted in rat cardiac myocytes (RCMs) stimulated with the supernatant from LPS/ATP-treated rat cardiac fibroblasts (RCFs). Pretreatment of the RCFs with VX765 (25 μM) reversed the downregulation of Cx43 expression in RCMs and significantly improved intercellular communication detected using a scrape-loading/dye transfer assay. We revealed that VX765 suppressed the activation of p38 MAPK signaling in the heart tissue after MI as well as in RCMs stimulated with the supernatant from LPS/ATP-treated RCFs. Taken together, these data show that the caspase-1 inhibitor VX765 upregulates Cx43 expression and improves cell-to-cell communication in rat heart after MI via suppressing the IL-1β/p38 MAPK pathway.
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APPLIED SURFACE SCIENCE
·
2022
·
IF 7.392
Yi Wang,Linhao Hou,Yiqian Huang,Pengfei Wei,Liya Sun,Yan Zhang,Xueqiao Yu,Shiqing Ma,Wei Jing,Bo Zhao,Huachong Ma
Chronic wounds in diabetes take a lifetime risk of developing into diabetic foot ulcers (DFUs). Conventional wound dressings and commercial products fail for ideal tissue regeneration in DFUs due to the incapacity to promote vascularization and prevent bacterial infections during wound repair. In this study, the small intestinal submucosa (SIS) with enriched vascularized bioactive factors, was chemically decorated by 2-methacryloyloxy ethyl phosphorylcholine (MPC) through Michael-type addition to be endowed anti-fouling ability, in order to treat chronic wound regeneration in diabetes. In the diabetic skin injury experiment, we established the animal model by 5-mm diameter defects in the SD rats and implanted the bio-patches to the located sites. The SIS-MPC bio-patch showed superior advantages in bacterial anti-adhesion (100-fold foul resistance than commercial patches), while maintained affinity for fibroblast growth and collagen formation, as demonstrated by immunohistochemical staining from the local tissues, outperforming commercial wound dressings in tissue regeneration, which was attributed to acceleration in neovascularization and inflammation modulation through TGF-β and MAPK pathway. This novel SIS-MPC bio-patch would be a promising candidate for medical translations into diabetes and chronic wound treatments.
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Foods
·
2025
·Vol. 14
·期 4
·619
·
IF 5.1
Kaijie Shang,Zhiheng Zhao,Hua Chen,Xiaonan Bian,Xianquan Zhong,Xiaoping Hu,Xue Lin,Lu Wang
The consumption of wampee has traditionally been utilized to alleviate gastrointestinal inflammation and associated disorders; however, its exact mechanism has remained unknown. The aim of this study was to elucidate the therapeutic efficacy and underlying mechanism of wampee polyphenol extract (WPE) in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). The findings revealed that WPE alleviated diverse symptoms of UC, regulated various inflammatory cytokines, and effectively protected the colon tissue structure and barrier integrity, thereby inhibiting LPS translocation. Moreover, WPE restored the richness and diversity of gut microbiota and optimized its structure at the phylum and genus levels, causing a notable improvement in short- chain fatty acid (SCFA) metabolism, particularly acetic acid, propionic acid, and butyric acid. Consequently, WPE was demonstrated to effectively suppress the LPS-induced TLR4-p38 MAPK/NF-κB signaling pathway by modulating gut microbiota and SCFA metabolism. These findings provided a theoretical basis for the use of wampee as a potential functional natural food for UC.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Chunyan Wang,Xu Huang,Kailing Sun,Xiang Li,Dingding Feng,Yoshimasa Nakamura,Hang Qi
Fucoxanthin (FX), a non-provitamin-A carotenoid, is a well-known major xanthophyll contained in edible brown algae. The nanoencapsulation of FX was motivated due to its multiple activities. Here, nano-encapsulated-FX (nano-FX) was prepared according to our early method by using whey protein and flaxseed gum as the biomacromolecule carrier material, then in vivo antitumor effect and mechanism of nano-FX on xenograft mice were investigated. Thirty 4-week-old male BALB/c nude mice were fed adaptively for 7 days to establish xenograft tumor model with Huh-7 cells. The tumor-bearing mice consumed nano-FX (50, 25, and 12.5 mg kg −1 ) and doxorubicin hydrochloride (DOX, 1 mg kg −1 ) or did not consume (Control) for 21 days, n = 6. The tumor inhibition rates of nano-FX were as high as 54.67 ± 1.04 %. Nano-FX intervention promoted apoptosis and induced hyperchromatic pyknosis and focal necrosis in tumor tissue by down-regulating the expression of p-JNK, p-ERK, PI3Kp85α, p-AKT, p-p38MAPK, Bcl-2, CyclinD1 and Ki-67, while up-regulating the expression of cleaved caspase-3 and Bax. Nano-FX inhibited tumor growth and protected liver function of tumor bearing mice in a dose-dependent manner, up-regulate the level of apoptosis-related proteins, inhibit the MAPK-PI3K/Akt pathways, and promote tumor cell apoptosis.
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FOOD RESEARCH INTERNATIONAL
·
2025
·
IF 8
Ziyi Shen,Simeng Zhou,Yaru Zhang,Yuan Zhang,Hongyan Wang,Daxiang Li,Yijun Wang,Zhongwen Xie,Huifang Ge
Large-leaf yellow tea protein-derived oligopeptides (TPP) contain a substantial number of antioxidant peptides that facilitate skin damage repair and may be employed to mitigate skin photoaging. However, the potential alleviating mechanism by which TPP alleviates skin photoaging damage remains insufficiently understood. This study investigated the in vitro antioxidant capacity and cell migration-promoting ability of TPP. Additionally, it utilized ultraviolet (UV)-exposed and intrinsically aged ICR mice, which exhibit signs of skin aging, to assess the effects of an 8-week oral TPP intervention. The findings indicate that TPP exhibits potent free radical scavenging properties, which mitigate oxidative damage in Raw264.7 cells and promote the migration of NIH/3 T3 cells. TPP intervention significantly ameliorates oxidative stress and skin inflammation symptoms in UV-induced skin photoaging damage by restoring the activity of endogenous antioxidant enzymes and suppressing the mRNA expression of pro-inflammatory cytokines, including IL-1β , IL-6 , and TNF-α ., as well as inhibiting the MAPK/AP-1/MMP9 signaling pathways. This study proposes that TPP is a viable plant protein-derived nutritional supplement for the prevention of UV-induced skin photoaging damage.
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Journal of Ocean University of China
·
2024
·Vol. 23
·期 6
·1615-1629
·
IF 1.4
Wang Wenwen,Wei Shu,Chen Yadong,Tan Suxu,Shi Kunpeng,Zang Shaoqing,Wang Minmin,Yang Teng,Yang Yingming,Cui Zhongkai,Sha Zhenxia
As an efficient immunostimulant, chitosan oligosaccharide (COS) can enhance the immunity of teleosts; however, the underlying molecular mechanisms still require elucidation. Competing endogenous RNAs (ceRNAs) are vital regulators in the immune response, but their roles in half-smooth tongue sole ( Cynoglossus semilaevis ) remain unclear. In this study, for the first time, we studied whole-transcriptome expression profiles and analyzed ceRNA networks in peripheral blood leukocytes of half-smooth tongue sole treated with COS. A total of 19 circRNAs (DE-circRNAs), 18 miRNAs (DE-miRNAs) and 50 previously identified lncRNAs (DE-lncRNAs) were differentially expressed after COS stimulation. The DE-lncRNAs and DE-miRNAs targeted numerous immunity-related genes, and were enriched in important pathways, including MAPK and Toll-like receptor signaling pathways, suggesting the immunoregulatory roles of COS. Furthermore, we constructed circRNA-miRNA-mRNA and lncRNA-miRNA-mRNA regulatory networks using DE-circRNAs, DE-miRNAs, DE-lncRNAs, and DE-mRNAs. Additionally, a ceRNA network with immunity-related DE-mRNAs was constructed, showing that 3 DE-circRNAs, 12 DE-lncRNAs, and 29 DEGs exhibited crosstalk through 9 DE-miRNAs. Intriguingly, a DE-miRNA in the ceRNA network, miR-144-3p, was targeted by DE-lncRNA tnrc6a , and negatively regulated the genes of inhibitor of nuclear factor kappa B kinases (IKKs) ( ikbkg , ikbkb , and ikbip ) and c3ar1 . Ikbkg , ikbkb , and c3ar1 were significantly up-regulated in macrophages stimulated by LPS. It could be inferred that ncRNAs participated in the immune and inflammatory response by acting as ceRNAs after COS stimulation in teleosts. These findings indicate that COS could enhance the immunity of teleosts by regulating ncRNAs, and lay the foundation for further practical application of COS in aquaculture.
研究领域:
免疫学
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分子生物学
·
水产养殖
·
转录组学
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2021
·
IF 4.36
Feng-mao An,Zheng Liu,Xin-ran Xuan,Qing-shan Liu,Cheng-xi Wei
Ethnopharmacological relevance The traditional Chinese medicine Sanweidoukou decoction (DK-3) was a classical formula for the treatment of nervous system diseases , recorded in the Chinese medical classic Sibu Yidian . Aim of the study The present study is aim to investigate the neuroprotective effects of DK-3 on β-amyloid (Aβ) protein -induced AD-like pathologies and underlying molecular mechanisms both in vitro and in vivo studies. Materials and methods Hydrolysates of DK-3 were analyzed by LC-ESI-MS/MS. In vitro , MTT was utilized to examine effects of DK-3 on Aβ 25-35 -induced cytotoxicity in PC12 cells. In vivo , male Sprague-Dawley rats were administered with Aβ 25-35 to induce AD-like pathologies and behavioral evaluations were conducted via Morris water maze (MWM) test. Histopathological changes were observed by Hematoxylin-eosin (HE) straining. Immunohistochemistry (IHC) was used to detect the tau hyperphosphorylation at Thr181 site. The expression levels of tau hyperphosphorylation, inflammation-related cytokines such as COX-2, iNOS , TNF-α, IL-1β, IL-6, the phosphorylated state of various mitogen-activated protein kinase (MAPK) signaling molecules (p38 MAPK, ERK, and JNK) and activation of nuclear factor κB (NF-κB) in vitro and in vivo were assessed via Western blot . Results In vitro , DK-3 dose-dependently increased cell viability of PC12 cells induced by Aβ 25-35 . In vivo , DK-3 improved learning and memory abilities of Aβ 25-35 -induced AD-like rats. Moreover, DK-3 reversed hyperphosphorylation of tau and reduced the production of inflammation-related cytokines through significantly inhibited MAPK and NF-κB signaling pathways both in vitro and in vivo studies. Conclusion The present study suggested that the traditional Chinese medicine DK-3 may play a role in preventing and treating AD by reducing the hyperphosphorylation of tau protein and the expressions of inflammation-related cytokines via modulating the MAPK/NF-κB signaling pathways.
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Bioengineered
·
2021
·
IF 3.269
Haixia Liu,Mei Song,Xiaoyan Sun,Xin Zhang,Huayan Miao,Yankui Wang
Cervical cancer (CC) is the fourth most common cancers among women worldwide. T-box transcription factor 1 (TBX1), a member of the T-box family, has anti-tumor effects in some types of cancer, but its role in CC is yet unknown. The aim of this study is to investigate the functions and underlying mechanisms of TBX1 in CC. Online database UALCAN showed that TBX1 was down-regulated in CC tissues compared with normal tissues and patients with lower TBX1 expression level had a poor prognosis. TBX1 overexpression significantly decreased the proliferation, migration, and invasion of Hela and SiHa cells. Conversely, cell apoptosis and chemosensitivity to cisplatin were promoted in TBX1-overexpressing CC cells. Moreover, up-regulation of TBX1 inhibited both AKT and MAPK signaling pathways. Furthermore, dual luciferase report assay indicated that TBX1 could directly bind to miR-6727-5p. In addition, TBX1 expression was inhibited by miR-6727-5p mimic and up-regulated by miR-6727-5p inhibitor. Knockdown of TBX1 reversed the inhibitory effect of the miR-6727-5p inhibitor on CC cells. This study demonstrates that TBX1, a target gene of miR-6727-5p, acts as a tumor suppressor in CC, indicating that TBX1 may be a new target for CC therapy.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2018
·
IF 4.816
Long Ma,Yuanyuan Meng,Chunhao Tu,Xiuqi Cao,Haiyue Wang,Yuyin Li,Shuli Man,Jin Zhou,Miao Li,Zhenxing Liu,Yanfang Su
Experiments have been undertaken and for the first time, we have identified that a new cardiac glycoside (CG) isolated from Helleborus thibetanus Franch. a plant endemic to China, bears potent anti-cancer activity. We have named it as HTF-1. By using in vitro cell models, we have found that HTF-1 induces apoptosis against several types of cancer cells in a concentration- and time-dependent manner. It is able to inhibit cancer cell in proliferation, migration and invasion. HTF-1 causes S cell cycle arrest . Further-on, we have identified that HTF-1 triggers caspase-9 dependent apoptosis pathway and double strand DNA breaks (DSBs). Additionally, HTF-1 activates JNK , but suppresses ERK and PI3K-Akt-mTOR pathways. Collectively, the above-mentioned mechanisms contribute to the anti-cancer activity of HTF-1. It is rare to discover novel anti-cancer CG during the past couple of decades. We believe that our work will enrich the understanding of CGs; also, pave the way for natural product-based anti-cancer drug development.
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